Lymphatic vessels can transport fluid either by pressure-driven flow or by active pumping, even against gravity when necessary. In normal physiology, the lymphatic system is able to use these mechanisms to effectively and dynamically maintain tissue fluid homeostasis. In some diseases, however, lymphatic function is inefficient, resulting in tissue edema and weakened immune response. Because the mechanisms that control lymphatic function are not well-understood, we currently have no effective therapies that can restore lymphatic function in these patients. We propose that transport of lymph is controlled by complementary mechanobiological mechanisms involving Ca2+ fluxes and nitric oxide. We will test this hypothesis by developing a computational model of lymphatic transport and tissue fluid dynamics. We will then validate the simulations in a mouse model of lymphatic function and use it to identify and test novel treatments for edema and impaired lymph flow.